Abstract
Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, this synergy enhances bundling and spatially arranges microtubules. We further show that different Tau condensates efficiently induce pathological Tau in cells, including small accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations, and a condensate-like density for nuclear envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations and Definitions
- AD
- Alzheimer’s disease
- CFP
- cyan fluorescent protein
- DLS
- dynamic light scattering
- FTD
- frontotemporal dementia
- LLPS
- liquid-liquid phase separation
- MTs
- microtubules
- R0
- radius of hydration (Stokes radius)
- YFP
- yellow fluorescent protein
- FRAP
- fluorescence recovery after photobleaching
- FLIM
- fluorescence lifetime imaging microscopy
- FRET-FLIM
- Foerster Resonance energy transfer measured by FLIM of the donor
- CYT
- cytosolic Tau inclusions
- NUC
- intranuclear Tau accumulations
- NE
- Tau accumulations at the nuclear envelope
- hepAGG
- Tau aggregated in the presence of heparin at a 4:1 (Tau:heparin) ratio
- mesoscopic clusters
- R0 ∼100-200 nm
- microscopic condensates
- R0 ∼1000 nm
- monomeric/clusters/condensates
- refers to degree of Tau assembling
- Tau coacervation
- LLPS driven by interaction of Tau with polyanions in the presence of PEG
- Tau condensation
- term for all LLPS processes